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Preterm neonates undergo numerous painful procedures in the neonatal intensive care unit (NICU). Sucrose, with and without pacifiers, is effective and safe for relieving pain from single painful events. However, repeated use of sucrose for multiple painful procedures has not been adequately evaluated. The study objectives were to: 1) determine the efficacy and safety of consistent management of repeated procedural pain with sucrose; and 2) explore the impact of consistent pain management on clinical outcomes and neurobiological risk status.Sixty-six preterm infants were randomized to receive standard care (positioning and swaddling; n = 21), sterile water plus pacifier (n = 23), or 24% sucrose plus pacifier (n = 22) prior to all painful procedures in the NICU during the first 28 days of life. Also, at a routine heel lance at 7, 14, 21, and 28 days of life, data were collected to determine efficacy and immediate and long-term adverse events. Data on clinical outcomes and neurobiological risk status were collected at 28 days or NICU discharge.There was no intervention by time interaction (P = 0.60). There was a significant main effect of intervention (P = 0.03) between the sucrose plus pacifier group, and the standard care group (P = 0.01), but there was no main effect of time (P = 0.72). No group differences existed for adverse events, clinical outcomes, or neurobiological risk status.Consistent management of painful procedures with sucrose plus pacifier was effective and safe for preterm neonates during their stay in the NICU. Further exploration of consistent pain management with sucrose on clinical, developmental, and neurobiological outcomes is required.